In salt-sensitive subjects, high salt intake results in increased central sympathetic outflow, sodium retention and hypertension. We demonstrate brain G1i2-subunit proteins mediate the sympathoinhibitory, cardiovascular and renal excretory responses to central GPCR-activation and attenuate hypertension in salt-resistant subjects. This application will test the overall hypothesis that PVN G1i2-subunit protein-gated pathways play a critical role in the central neural control of sodium and water excretion and systemic arterial blood pressure regulation. Endogenous up-regulation of PVN G1i2 proteins in response to increased salt-intake will potentiate endogenous sympathoinhibitory mechanisms to counter the development of salt-sensitive hypertension whereas failure to endogenously up-regulate PVN G1i2 proteins will exacerbate blood pressure dysregulation. The following Specific Aims will be conducted: Specific Aim 1: To establish that 1) brain G1i2-subunit protein- gated pathways mediate centrally-evoked renal sympathoinhibitory responses to physiological and pharmacological stimuli and, 2) central G1i2-subunit proteins are endogenously up-regulated as a counter regulatory mechanism to attenuate the development of salt-sensitive hypertension in Sprague-Dawley rats. Specific Aim 2: To establish the PVN as a specific brain site in which G1i2-subunit proteins are endogenously up-regulated to potentiate renal sympathoinhibitory and natriuretic pathways to maintain fluid and electrolyte homeostasis and counter the development of salt-sensitive hypertension in Sprague-Dawley rats. Specific Aim 3: To establish that 1) failure to up-regulate PVN G1i2-subunit proteins, in response to high-salt intake, leads to attenuation of endogenous counter-regulatory renal sympathoinhibitory and natriuretic responses and salt- sensitive hypertension in Dahl salt-sensitive rats, and 2) PVN specific gene therapy to over express G1i2- subunit proteins will restore renal sympathoinhibitory and natriuretic mechanisms and attenuate the development of Dahl salt-sensitive hypertension. These studies are central to the mission of National Heart Lung and Blood Institute, which is to promote the prevention and treatment of heart, lung and blood disease, and directly support the NHLBI Strategic Plan of improving understanding of molecular and physiological basis of health and disease. Specific Aims 1 & 2 will remove the influence of brain, and specifically PVN, G1i2 proteins using oligodeoxynucleotides (ODN's) to determine the role(s) of G1i2 proteins in the central regulation of renal sympathetic nerve activity, fluid and electrolyte homeostasis, and blood pressure in response to acute pharmacological & physiological stimuli (central 12-adrenoceptor & GABAB stimulation, i.v. volume expansion) or the integrated physiological stimulus of chronic high salt-intake in Sprague-Dawley rats. Specific Aim 3 will define the role of PVN G1i2 proteins, via an ODN and lentiviral gene therapy approach, in the Dahl rat model of salt-sensitive hypertension. These innovative studies will further the fields of CNS autonomic regulation and hypertension research and potentially lead to the identification of new therapeutic targets for hypertension. PUBLIC HEALTH RELEVANCE: Hypertension, a condition affecting 1 in 3 US adults, caused approximately 326,000 US deaths in 2006 and is predicted to be the leading global cause of death by the year 2020. This project will establish why certain individuals are resistant to increases in blood pressure caused by dietary salt intake and will potentially lead to the development of new therapeutics to prevent the development of salt-sensitive hypertension.